Biogenic selenium nanoparticles alleviate intestinal barrier injury in mice through TBC1D15/Fis1/Rab7 pathway.

Intestinal diseases often stem from a compromised intestinal barrier. This barrier relies on a functional epithelium and proper turnover of intestinal cells, supported by mitochondrial health. Mitochondria and lysosomes play key roles in cellular balance. Our previous researches indicate that biogenic selenium nanoparticles (SeNPs) can alleviate intestinal epithelial barrier damage by enhancing mitochondria-lysosome crosstalk, though the detailed mechanism is unclear. This study aimed to investigate the role of mitochondria-lysosome crosstalk in the protective effect of SeNPs on intestinal barrier function in mice exposed to lipopolysaccharide (LPS). The results showed that LPS exposure increased intestinal permeability in mice, leding to structural and functional damage to mitochondrial and lysosomal. Oral administration of SeNPs significantly upregulated the expression levels of TBC1D15 and Fis1, downregulated the expression levels of Rab7, Caspase-3, Cathepsin B, and MCOLN2, effectively alleviated LPS-induced mitochondrial and lysosomal dysfunction and maintained the intestinal barrier integrity in mice. Furthermore, SeNPs notably inhibited mitophagy caused by adenovirus-associated virus (AAV)-mediated RNA interference the expression of TBC1D15 in the intestine of mice, maintained mitochondrial and lysosomal homeostasis, and effectively alleviated intestinal barrier damage. These results suggested that SeNPs can regulate mitochondria-lysosome crosstalk and inhibit its damage by regulating the TBC1D15/Fis1/Rab7- signaling pathway. thereby alleviating intestinal barrier damage. It lays a theoretical foundation for elucidating the mechanism of mitochondria-lysosome crosstalk in regulating intestinal barrier damage and repair, and provides new ideas and new ways to establish safe and efficient nutritional regulation strategies to prevent and treat intestinal diseases caused by inflammation.

Replacing dietary sodium selenite with biogenic selenium nanoparticles improves the growth performance and gut health of early-weaned piglets.

Selenium nanoparticles (SeNPs) are proposed as a safer and more effective selenium delivery system than sodium selenite (Na2SeO3). Here, we investigated the effects of replacing dietary Na2SeO3 with SeNPs synthesized by Lactobacillus casei ATCC 393 on the growth performance and gut health of early-weaned piglets. Seventy-two piglets (Duroc × Landrace × Large Yorkshire) weaned at 21 d of age were divided into the control group (basal diet containing 0.3 mg Se/kg from Na2SeO3) and SeNPs group (basal diet containing 0.3 mg Se/kg from SeNPs) during a 14-d feeding period. The results revealed that SeNPs supplementation increased the average daily gain (P = 0.022) and average daily feed intake (P = 0.033), reduced (P = 0.056) the diarrhea incidence, and improved (P = 0.013) the feed conversion ratio compared with Na2SeO3. Additionally, SeNPs increased jejunal microvilli height (P = 0.006) and alleviated the intestinal barrier dysfunction by upregulating (P < 0.05) the expression levels of mucin 2 and tight junction proteins, increasing (P < 0.05) Se availability, and maintaining mitochondrial structure and function, thereby improving antioxidant capacity and immunity. Furthermore, metabolomics showed that SeNPs can regulate lipid metabolism and participate in the synthesis, secretion and action of parathyroid hormone, proximal tubule bicarbonate reclamation and tricarboxylic acid cycle. Moreover, SeNPs increased (P < 0.05) the abundance of Holdemanella and the levels of acetate and propionate. Correlation analysis suggested that Holdemanella was closely associated with the regulatory effects of SeNPs on early-weaned piglets through participating in lipid metabolism. Overall, replacing dietary Na2SeO3 with biogenic SeNPs could be a potential nutritional intervention strategy to prevent early-weaning syndrome in piglets.

Lactobacillus casei ATCC 393 combined with vasoactive intestinal peptide alleviates dextran sodium sulfate-induced ulcerative colitis in C57BL/6 mice via NF-κB and Nrf2 signaling pathways.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) which is related to an immunological imbalance of the intestinal mucosa. Many clinical evidences indicate probiotics supplementation appears to be effective and safe in patients with UC. Vasoactive intestinal peptide (VIP) is an endogenous neuropeptide with multiple physiological and pathological effects. In this study, we investigated the protective effect of the combination of Lactobacillus casei ATCC 393 (L. casei ATCC 393) with VIP on dextran sodium sulfate (DSS)-induced UC in mice and the potential mechanism. The results showed that, compared with the control group, DSS treatment significantly shortened the colon length, caused inflammation and oxidative stress, and further resulted in the intestinal barrier dysfunction and gut microbiota dysbiosis. In addition, intervention with L. casei ATCC 393, VIP or L. casei ATCC 393 combined with VIP significantly reduced UC disease activity index. However, compared with L. casei ATCC 393 or VIP, L. casei ATCC 393 combined with VIP effectively relieved symptoms of UC by regulating immune response, enhancing antioxidant capacity, and regulating nuclear factor kappa-B (NF-κB) and nuclear factor erythroid-derived-2-like 2 (Nrf2) signaling pathways. In conclusion, this study suggests that L. casei ATCC 393 combined with VIP can effectively relieve DSS-induced UC, which is a promising treatment strategy for UC.

Biogenic selenium nanoparticles alleviate intestinal epithelial barrier injury by regulating mitochondria-lysosome crosstalk.

The intestinal epithelial barrier plays a fundamental role in human and animal health. Mitochondrial dysfunction can lead to intestinal epithelial barrier damage. The interaction between mitochondria and lysosomes has been proved to regulate each other's dynamics. Our previous studies have demonstrated that biogenic selenium nanoparticles (SeNPs) can alleviate intestinal epithelial barrier injury through regulating mitochondrial autophagy. In this study, we hypothesize that the protective effects of SeNPs against intestinal epithelial barrier dysfunction are associated with mitochondrial-lysosomal crosstalk. The results showed that lipopolysaccharide (LPS) and TBC1D15 siRNA transfection both caused the increase of intestinal epithelial permeability, activation of mitophagy, and mitochondrial and lysosomal dysfunction in porcine jejunal epithelial cells (IPEC-J2). SeNP pretreatment significantly up-regulated the expression levels of TBC1D15 and Fis1, down-regulated Rab7, caspase-3, MCOLN2 and cathepsin B expression levels, reduced cytoplasmic Ca2+ concentration, effectively alleviated mitochondrial and lysosomal dysfunction, and maintained the integrity of the intestinal epithelial barrier in IPEC-J2 cells exposed to LPS. Furthermore, SeNPs obviously reduced cytoplasmic Ca2+ concentration and activated the TBC1D15/Fis/Rab7-mediated signaling pathway, shortened the contact time between mitochondria and lysosomes, inhibited mitophagy, maintained mitochondrial and lysosomal homeostasis, and effectively attenuated intestinal epithelial barrier injury in IPEC-J2 cells transfected with TBC1D15 siRNA. These results indicated that the protective effect of SeNPs on intestinal epithelial barrier injury is closely associated with the TBC1D15/Rab7-mediated mitochondria-lysosome crosstalk signaling pathway.

Selenite Bioremediation by Food-Grade Probiotic Lactobacillus casei ATCC 393: Insights from Proteomics Analysis.

Microorganisms capable of converting toxic selenite into elemental selenium (Se0) are considered an important and effective approach for bioremediation of Se contamination. In this study, we investigated the mechanism of reducing selenite to Se0 and forming Se nanoparticles (SeNPs) by food-grade probiotic Lactobacillus casei ATCC 393 (L. casei ATCC 393) through proteomics analysis. The results showed that selenite added during the exponential growth period of bacteria has the highest reduction efficiency, and 4.0 mM selenite decreased by nearly 95% within 72 h and formed protein-capped-SeNPs. Proteomics analysis revealed that selenite induced a significant increase in the expression of glutaredoxin, oxidoreductase, and ATP binding cassette (ABC) transporter, which can transport glutathione (GSH) and selenite. Selenite treatment significantly increased the CydC and CydD (putative cysteine and glutathione importer, ABC transporter) mRNA expression level, GSH content, and GSH reductase activity. Furthermore, supplementation with an additional GSH significantly increased the reduction rate of selenite, while GSH depletion significantly inhibited the reduction of selenite, indicating that GSH-mediated Painter-type reaction may be the main pathway of selenite reduction in L. casei ATCC 393. Moreover, nitrate reductase also participates in the reduction process of selenite, but it is not the primary factor. Overall, L. casei ATCC 393 effectively reduced selenite to SeNPs by GSH and nitrate reductase-mediated reduction pathway, and the GSH pathway played the decisive role, which provides an environmentally friendly biocatalyst for the bioremediation of Se contamination. IMPORTANCE Due to the high solubility and bioavailability of selenite, and its widespread use in industrial and agricultural production, it is easy to cause selenite to accumulate in the environment and reach toxic levels. Although the bacteria screened from special environments have high selenite tolerance, their safety has not been fully verified. It is necessary to screen out strains with selenite-reducing ability from nonpathogenic, functionally known, and widely used strains. Herein, we found food-grade probiotic L. casei ATCC 393 effectively reduced selenite to SeNPs by GSH and nitrate reductase-mediated reduction pathway, which provides an environmentally friendly biocatalyst for the bioremediation of Se contamination.

Metabolic heterogeneity in early-stage lung adenocarcinoma revealed by RNA-seq and scRNA-seq.

PURPOSE: Cancer cells maintain cell growth, division, and survival through altered energy metabolism. However, research on metabolic reprogramming in lung adenocarcinoma (LUAD) is limited METHODS: We downloaded TCGA and GEO sequencing data. Consistent clustering with the ConsensusClusterPlus package was employed to detect the scores for four metabolism-related pathways. The LUAD samples in the TCGA dataset were clustered with ConsensusClusterPlus, and the optimal number of clusters was determined according to the cumulative distribution function (CDF). The cell score for each sample in the TCGA dataset was calculated using the MCPcounter estimate function of the MCPcounter package. RESULTS: We identified two subtypes by scoring the samples based on the 4 metabolism-related pathways and cluster dimensionality reduction. The prognosis of cluster B was obviously poorer than that of cluster A in patients with LUAD. The analysis of single-nucleotide variation (SNV) data showed that the top 15 genes in the four metabolic pathways with the most mutations were TKTL2, PGK2, HK3, EHHADH, GLUD2, PKLR, TKTL1, HADHB, CPT1C, HK1, HK2, PFKL, SLC2A3, PFKFB1, and CPT1A. The IFNγ score of cluster B was significantly higher than that of cluster A. The immune T-cell lytic activity score of cluster B was significantly higher than that of cluster A. We further identified 5 immune cell subsets from single-cell sequencing data. The top 5 marker genes of B cells were IGHM, JCHAIN, IGLC3, IGHA1, and IGKC. The C0 subgroup of monocytes had a higher pentose phosphate pathway (PPP) score than the C6 subgroup. CONCLUSIONS: Metabolism-related subtypes could be potential biomarkers in the prognosis prediction and treatment of LUAD.

Biogenic Selenium Nanoparticles Synthesized by Lactobacillus casei ATCC 393 Alleviate Acute Hypobaric Hypoxia-Induced Intestinal Barrier Dysfunction in C57BL/6 Mice.

Exposure to hypobaric hypoxia at high altitude will cause different tissue and organ damage over a long period of time. Studies have shown that hypobaric hypoxia can cause severe primary intestinal barrier dysfunction, and then cause multiple organ dysfunction. Our previous research showed that selenium nanoparticles (SeNPs) synthesized by Lactobacillus casei ATCC 393 (L. casei ATCC 393) can effectively alleviate intestinal barrier dysfunction caused by oxidative stress and inflammation in mice. This study was conducted to investigate the protective effect of biological SeNPs synthesized by L. casei ATCC 393 on intestinal barrier function in acute hypobaric hypoxic stress mice. The results showed that compared with the hypobaric hypoxic, the SeNPs synthesized by L. casei ATCC 393 by oral administration could effectively alleviate the shortening of intestinal villi, which decreased the level of diamine oxidase (DAO) and myeloperoxidase (MPO), and the expression level of tight junction protein in ileum was increased. In addition, SeNPs significantly increased the activities of superoxide dismutase (SOD), cyclooxygenase (COX-1) and glutathione peroxidase (GPx), and decreased the level of malondialdehyde (MDA), and inhibit the increase of hypoxia related factor. SeNPs effectively regulate the intestinal microecology disorder caused by hypobaric hypoxia stress, and maintain the intestinal microecology balance. In addition, oral administration of SeNPs had better protective effect on intestinal barrier function of mice under hypobaric hypoxia stress. These results suggested that SeNPs synthesized by L. casei ATCC 393 can effectively alleviate the damage of intestinal barrier function under acute hypobaric hypoxic stress, which may be closely related to the antioxidant activity of SeNPs.

Protective effect of biogenic selenium nanoparticles against diquat-induced acute toxicity via regulation of gut microbiota and its metabolites.

Selenium nanoparticles (SeNPs) with unique biological properties have been suggested as a safer and more effective platform for delivering of Selenium for biological needs. In this study, we investigated the association between gut microbiota altered by SeNPs supplementation and its metabolites under oxidative stress conditions through 16S rDNA gene sequencing analysis and untargeted metabolomics. The results showed that dietary supplementation with SeNPs attenuated diquat-induced acute toxicity in mice, as demonstrated by lower levels of inflammatory effector cells, and biochemical markers in serum such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN) and lactate dehydrogenase (LDH). SeNPs also reversed the perturbed gut microbiota composition induced by diquat, decreased the Firmicutes/Bacteroidetes ratio, and increased the abundance of beneficial bacteria such as Akkermansia, Muribaculaceae, Bacteroides and Parabacteroides. Untargeted fecal metabolomics showed that SeNPs can regulate the production of steroids and steroid derivatives, organonitrogen compounds, pyridines and derivatives and other metabolites. Microbiome-metabolome correlation analysis suggested that Parabacteroides was the key bacteria for the SeNPs intervention, which might upregulate the levels of metabolites such as trimethaphan, emedastine, berberine, desoxycortone, tetrahydrocortisone. This study demonstrated that dietary SeNPs supplementation can extensively modulate the gut microbiota and its metabolism, thereby alleviating diquat-induced acute toxicity.

Regulatory mechanisms and potential medical applications of HNF1A-AS1 in cancers.

Long noncoding RNAs (lncRNAs) are defined as a class of non-protein-coding RNAs that are longer than 200 nucleotides. Previous studies have shown that lncRNAs play a vital role in the progression of multiple diseases, which highlights their potential for medical applications. The lncRNA hepatocyte nuclear factor 1 homeobox A (HNF1A) antisense RNA 1 (HNF1A-AS1) is known to be abnormally expressed in multiple cancers. HNF1A-AS1 exerts its oncogenic roles through a variety of molecular mechanisms. Moreover, aberrant HNF1A-AS1 expression is associated with diverse clinical features in cancer patients. Therefore, HNF1A-AS1 is a promising biomarker for tumor diagnosis and prognosis and thus a potential candidate for tumor therapy. This review summarizes current studies on the role and the underlying mechanisms of HNF1A-AS1 various cancer types, including gastric cancer, liver cancer, glioma, lung cancer, colorectal cancer, breast cancer, bladder cancer, osteosarcoma, esophageal adenocarcinoma, hemangioma, oral squamous cell carcinoma, laryngeal squamous cell carcinoma, cervical cancer, as well as gastroenteropancreatic neuroendocrine neoplasms. We also describe the diagnostic, prognostic, and therapeutic value of HNF1A-AS1 for multiple cancer patients.

Dietary supplementation with biogenic selenium nanoparticles alleviate oxidative stress-induced intestinal barrier dysfunction.

Selenium (Se) is an essential micronutrient that promotes body health. Endemic Se deficiency is a major nutritional challenge worldwide. The low toxicity, high bioavailability, and unique properties of biogenic Se nanoparticles (SeNPs) allow them to be used as a therapeutic drug and Se nutritional supplement. This study was conducted to investigate the regulatory effects of dietary SeNPs supplementation on the oxidative stress-induced intestinal barrier dysfunction and its association with mitochondrial function and gut microbiota in mice. The effects of dietary SeNPs on intestinal barrier function and antioxidant capacity and its correlation with gut microbiota were further evaluated by a fecal microbiota transplantation experiment. The results showed that Se deficiency caused a redox imbalance, increased the levels of pro-inflammatory cytokines, altered the composition of the gut microbiota, and impaired mitochondrial structure and function, and intestinal barrier injury. Exogenous supplementation with biogenic SeNPs effectively alleviated diquat-induced intestinal barrier dysfunction by enhancing the antioxidant capacity, inhibiting the overproduction of reactive oxygen species (ROS), preventing the impairment of mitochondrial structure and function, regulating the immune response, maintaining intestinal microbiota homeostasis by regulating nuclear factor (erythroid-derived-2)-like 2 (Nrf2)-mediated NLR family pyrin domain containing 3 (NLRP3) signaling pathway. In addition, Se deficiency resulted in a gut microbiota phenotype that is more susceptible to diquat-induced intestinal barrier dysfunction. Supranutritional SeNPs intake can optimize the gut microbiota to protect against intestinal dysfunctions. This study demonstrates that dietary supplementation of SeNPs can prevent oxidative stress-induced intestinal barrier dysfunction through its regulation of mitochondria and gut microbiota.

Expression and crucial role of long non-coding RNA FGD5-AS1 in human cancers.

Long non-coding RNAs (lncRNAs) are transcribed by RNA polymerase II and are longer than 200 nucleotides. Several studies have revealed that lncRNAs are important regulators of cancer progression. The lncRNA FGD5-AS1, first identified in 2018, has emerged as a crucial regulator of processes related to carcinogenesis. The expression levels of FGD5-AS1 are known to be significantly up-regulated in a variety of human cancers. Moreover, FGD5-AS1 expression closely correlates with clinical features and poor prognosis and its expression has been shown to attenuate cell proliferation, cell migration, cell invasiveness, drug resistance, and the epithelial-mesenchymal transition through several pathways. Here, we provide an overview of the role of FGD5-AS1 in various cancers and discuss its potential clinical utility in tumor progression. In addition, we used a gene expression profiling interactive analysis dataset to explore associations between FGD5-AS1 pan-cancer expressions and prognoses.

Combined DNA Methylation and Transcriptomic Assessments to Determine a Prognostic Model for PD-1-Negative Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) has the highest incidence and mortality of any malignancy in the world. Immunotherapy has been a major breakthrough for HCC treatment, but immune checkpoint inhibitors (ICIs) are effective in only a small percentage of HCC patients. In the present study, we screened programmed cell death protein 1 (PD-1) -negative HCC samples, which are frequently resistant to ICIs, and identified their methylation and transcription characteristics through the assessment of differential gene methylation and gene expression. We also screened for potential targeted therapeutic drugs using the DrugBank database. Finally, we used a LASSO (least absolute shrinkage and selection operator) regression analysis to construct a prognostic model based on three differentially methylated and expressed genes (DMEGs). The results showed that ESTIMATE (Estimation of Stromal and Immune Cells in Malignant Tumors using Expression Data) scores for the tumor samples were significantly lower compared to normal sample ESTIMATE scores. In addition, we identified 31 DMEGs that were able to distinguish PD-1-negative samples from normal samples. A functional enrichment analysis showed that these genes were involved in a variety of tumor-related pathways and immune-related pathways, and the DrugBank screening identified potential therapeutic drugs. Finally, the prognostic model based on three DMEGs (UBD, CD5L, and CD213A2) demonstrated good predictive power for HCC prognosis and was verified using an independent cohort. The present study demonstrated the methylation characteristics of PD-1-negative HCC samples, identified several potential therapeutic drugs, and proposed a prognostic model based on UBD, CD5L, and CD213A2 methylation expression. In conclusion, this work provides an in-depth understanding of methylation in HCC samples that are not sensitive to ICIs.

Down-regulation of RBP4 indicates a poor prognosis and correlates with immune cell infiltration in hepatocellular carcinoma.

Recent research has indicated that metabolically related genes play crucial roles in the pathogenesis of hepatocellular carcinoma (HCC). We evaluated the associations between novel biomarkers and retinol-binding protein 4 (RBP4) for predicting clinical HCC outcomes, hub-related genes, pathway regulation, and immune cells infiltration. Bioinformatic analyses based on data from The Cancer Genome Atlas were performed using online analysis tools. RBP4 expression was low in HCC and was also down-regulated in pan-cancers compared with normal tissues. RBP4 expression was also significantly different based on age (41-60 years old versus 61-80 years old), and low RBP4 expression levels were associated with advanced tumor stages and grades. Higher RBP4 expression was associated with better overall survival time in HCC patients, and we identified a deletion-mutation rate of 1.4% in RBP4. We also identified ten co-expressed genes most related to RBP4 and explored the relationships between six hub genes (APOB, FGA, FGG, SERPINC1, APOA1, and F2) involved in RBP4 regulation. A pathway enrichment analysis for RBP4 indicated complement and coagulation cascades, metabolic pathways, antibiotic biosynthesis pathways, peroxisome proliferator-activated receptor signaling pathways, and pyruvate metabolism pathways. These results suggest that RBP4 may be a novel biomarker for HCC prognosis, and an indicator of low immune response to the disease.